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Author Topic: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach  (Read 142854 times)

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Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #250 on: April 12, 2012, 01:06:48 PM »
Here's an interesting article re: CalImmune --

http://rnaitherapeutics.blogspot.com/2011/07/solid-calimmune-dna-directed-rnai.html

Interesting post, Dr. SL.  I thought that the infused modified T-Cells *do* have an antiviral effect.  The theory is that not all of your T-Cells need to be modified -- just about -15-20% or so to bring the viral levels down.  Anyway, that's the thinking behind the two Sangamo trials underway at Quest.  One of the heterozygotes went UD in the first trial because nature gave him an advantage -- he had double the number of modified cells.  Cytoxan should increase the uptake for the non-heteros.

We'll know soon enough if it works as some patients have gotten their infusions and stopped their meds. 

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #251 on: April 19, 2012, 03:46:07 PM »
Recent slide presentation by Dr. Cannon (love her):

http://dcfar.med.miami.edu/documents/Dr_Cannon_-_CCR5_gene_knockout_in_hematopoietic_stem_cells_(1).pdf

The latter half is new and interesting.  Once again she says these mice go undetectable in 12 weeks after the stem cell transplant.

Of course, modifying T-Cells might work.  In about 2 months it'll be 12 weeks since the first heterozygotes stopped taking their meds.  That should be enough to know whether the T-Cell treatment works or not.  Of course, the results may come out long after that, particularly if they are not good.

Offline sensual1973

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #252 on: April 20, 2012, 04:10:29 AM »
mice.
God grant me the serenity to accept the things i can not change.

Offline bmancanfly

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #253 on: April 20, 2012, 10:15:33 AM »
There's never been a better time to be a mouse with HIV.
"The trouble with the world is that the stupid are cocksure and the intelligent are full of doubt."

 Bertrand Russell

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #254 on: May 04, 2012, 11:40:03 AM »
Reading through the Q&A on Sangamo's quarterly conference call I found, from Ed Lamphier (CEO):

"I think its realistic to think that we will have those trials accrued by the end of the year and data in the first half of 2013 is a realistic expectation."

This means that the data for the current trials (the hetero trial and the Cytoxan trial) will be available next year.  I'm guessing that they'll release the info at CROI 2013.

Also very interesting was this answer:

"As it relates to HIV however, I think that’s a program that we will view as something we would like to partner for pivotal trials and for commercialization. It’s a large patient population, therefore a fairy significant commercial manufacturing undertaking and its something that we’d like to bring a partner on for pivotal trials and commercialization."

What I found intriguing was that he's already thinking down the road -- towards manufacturing and commercialization.   Hmmm......


Offline wherehope

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #255 on: May 18, 2012, 11:35:08 PM »
Felt excited at first, but after read details feel down again. The modified cd4 will die after years and maybe few years, even functionally cured then need to re-cure again after a "short" period, regarding the cost and chemotherapy each time. The newly produced CD4 of immune system is still the same as the old ones with CCR5 on it. This is different than elite controller whose all 100% CD4 always lack ccr5 all time. Maybe the stem cells have more hope since it maybe extend the HAART free period longer?
« Last Edit: May 18, 2012, 11:42:49 PM by wherehope »

Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #256 on: May 19, 2012, 06:42:47 AM »
Felt excited at first, but after read details feel down again. The modified cd4 will die after years and maybe few years, even functionally cured then need to re-cure again after a "short" period, regarding the cost and chemotherapy each time. The newly produced CD4 of immune system is still the same as the old ones with CCR5 on it. This is different than elite controller whose all 100% CD4 always lack ccr5 all time. Maybe the stem cells have more hope since it maybe extend the HAART free period longer?

Uh....no.
Beware Romanians bearing strange gifts

Offline younghopefulpoz

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #257 on: May 19, 2012, 10:37:11 AM »
Maybe you should try bone marrow transplant, like Timothy brown.

Offline Tadeys

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #258 on: May 19, 2012, 01:05:25 PM »
Uh....no.

An Elite controller and someone who lacks the CCR5 gene are 2 separate entities. One has to do with antibodies and the other, with receptors on their cells.                       1) Every Elite contoller is HIV positive; they just CONTROL their infection to the point where it hardly does any harm to  their body.
2)It is dificult to find a person with the CCR5 mutation ( of BOTH copies) who IS HIV positive...they are pretty much immune from being infected with an HIV-1 Virus that uses ONLY the CCR5 receptor.
 
Also, ah, That Cd4 cells die out with in an X amount of time... Nothing new. Now Stem Cells do not die out and are always multiplying. Sooooo, for a cure:  1) More is better: the more cells without the CCR5 receptor the better. Knocking-out both receptors (CCR5 and CX4) would be best. 2) Stm Cells SEEM far more superior then cd4s for a CURE. Do we need both of these for a cure of sorts? Nobody knows for sure. Scientist stopped finding HIV In Brown a few months after the transplant...but he had virtually a new immune system after the treatment. The Trenton patient went undetected with just a few percent of his CD4s being zinc fingered...:).... don't get carried away AND please incluye a link next time. :P                                                                                                                    And another thing, would'nt count  on any one technique as being capable in and of itself in getting us to a cure. A combination of Medication + gen therapy + therapeutic vaccines will be a good bet. ciao.

Offline wherehope

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #259 on: May 19, 2012, 08:00:01 PM »
are you referring to zin finger? I wonder the modified T cells would die after a "short" period and would not multiplying. so how to cure?

Offline younghopefulpoz

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #260 on: May 19, 2012, 08:42:36 PM »
Why not just try to replicate the case of Berlin patient, it'll just be like treating leukemia. I wonder why they won't offer it to patients who can afford it. Now that it's been publicly announced that HIV is not incurable but a CURABLE. Big pharmas profit will end as soon as cure will be available.

Offline Miss Philicia

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #261 on: May 19, 2012, 09:04:28 PM »
I wonder why they won't offer it to patients who can afford it.

Because they want you to suffer for your sins.
"I’ve slept with enough men to know that I’m not gay"

Offline wherehope

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #262 on: May 19, 2012, 09:42:00 PM »
what sins? mistake is not sin!If it is, everybody has sins.

Offline wherehope

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #263 on: May 19, 2012, 09:47:24 PM »
I think the Berlin patient is a very rare case, the procedure is risky, and also it is hard to find the exact donor, maybe that is the reason they would not replicate it. Don't know when or ever there will be a cure, but let's hope. I read an article recently which said that possibly after 10 years around there will be a functional cure but eradication is longer.
« Last Edit: May 19, 2012, 09:50:16 PM by wherehope »

Offline younghopefulpoz

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #264 on: May 20, 2012, 01:13:19 AM »
They're not God to decide for us to suffer. Everybody got their own sins.

Offline Tadeys

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #265 on: May 20, 2012, 07:14:13 AM »
I think the Berlin patient is a very rare case, the procedure is risky, and also it is hard to find the exact donor, maybe that is the reason they would not replicate it. Don't know when or ever there will be a cure, but let's hope. I read an article recently which said that possibly after 10 years around there will be a functional cure but eradication is longer.

I think the study that came out a few weeks ago where scientist modified STEM cells into attacking and killing cells infected with HIV makes me think that even eradication is "just around the córner." As I'm writting this those same scientist are trying to make these cells even more potent and HIV trigger happy...Is'nt eradication of HIV infected cells in latency and HIV reservoirs the final piece of this puzzle in terms of a cure? If these cells can truly attack HIV EVERYWHERE in our bodies then we have a winner. Ciao.

Offline younghopefulpoz

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #266 on: May 20, 2012, 11:46:23 AM »
Yeah...

Offline wherehope

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #267 on: May 20, 2012, 07:37:18 PM »
Yeah...
Isn't it still in a mouse trial and find decreased hiv level? Hope they would go into human clinical trial next.

Offline wherehope

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #268 on: May 20, 2012, 07:37:51 PM »
I think the study that came out a few weeks ago where scientist modified STEM cells into attacking and killing cells infected with HIV makes me think that even eradication is "just around the córner." As I'm writting this those same scientist are trying to make these cells even more potent and HIV trigger happy...Is'nt eradication of HIV infected cells in latency and HIV reservoirs the final piece of this puzzle in terms of a cure? If these cells can truly attack HIV EVERYWHERE in our bodies then we have a winner. Ciao.
Isn't it still in a mouse trial and find decreased hiv level? Hope they would go into human clinical trial next.

Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #269 on: May 20, 2012, 09:15:10 PM »
Because they want you to suffer for your sins.

evil doers must be punished.
Beware Romanians bearing strange gifts

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #270 on: May 21, 2012, 12:28:00 PM »
I went in to get screened for both the Sangamo trials.  I wasn't a heterozygote -- so I wasn't eligible for the first trial.  But I held out hope for the second trial.  But I learned last week I'm not eligible for that one either.  Seems that my ratio (.9) was too low and my bilirubin was too high.  I found this a little frustrating -- they are looking for a ratio of 1 or above, which is a high bar and also I'm taking Reyataz so of course my bilirubin is high.  Duh!  Don't know why they put me through the whole process in the first place -- I could have told them that from the getgo.

It seems to me that in an effort to replicate the "Trenton" patient (the hetero who went UD) they are really trying to cherry pick who gets in the trials.  I suppose that makes sense.

I'm also being screened for the CalImmune trial, which should happen sometime this summer.  It's a stem cell treatment.  It's hard to find many articles on CalImmune. 


Offline Tadeys

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #271 on: May 21, 2012, 04:38:33 PM »
Hi geobee: new to this. 1) What do you mean by ratio? Cd4/cd8?
  2) I see much more potential in Callimmune with their RNAi than Sangamo and their zinc.
Ciao and thanks


Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #272 on: May 21, 2012, 06:20:24 PM »
Hey Tadeys,

Yes, the CD4/CD8 ratio.  At .9, I was doing pretty good...but not good enough.  They are looking for 1 or above (which is in the normal range I think).

CalImmune does look good.  But everything looks good from far away.  I know there are going to be three cohorts -- no chemo, mild chemo, moderate chemo.  The more chemo, the more the uptake of the new stem cells.  I should know more in a couple of months or so as I get closer to the screening.  I'm doing well on my meds, a little on the fence about partaking in CalImmune study if it's offered to me.

George
« Last Edit: May 22, 2012, 02:07:13 PM by geobee »

Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #273 on: May 22, 2012, 11:28:00 AM »
While I'm certainly not in a position to compare the science of the two companies, the sheer scientific firepower of Calimmune (www.calimmune.com) which has Nobel Laureate Dr. David Baltimore as it's Board Chairman and co-founder, is impressive.

A new day is dawning.
Beware Romanians bearing strange gifts

Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #274 on: May 30, 2012, 10:19:53 AM »
http://www.modernluxury.com/san-francisco/story/the-face-of-the-cure

Decent article, particularly for those new to this approach.  For my money the most interesting quote is on page 3 (bold mine):

I think we’ll totally be able to cure HIV in a sophisticated first-world setting,” says Paula Cannon, an associate professor of molecular microbiology and immunology at USC. “It’s going to take time and money, and a big challenge is going to be how to apply the cure broadly so it’s not just an expensive boutique treatment but one that can be mass-produced.”

Huh.

Beware Romanians bearing strange gifts

Offline freewillie99

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Beware Romanians bearing strange gifts

Offline younghopefulpoz

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #276 on: June 06, 2012, 12:53:27 PM »
promising :), thanks freewillie99 for the link.

Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #277 on: June 18, 2012, 07:51:54 PM »
Grassy knoll territory:

This week will be 12 weeks since the first 4 heterozygote participants in the latest Phase II Sangamo zinc finger trial stopped their medications after the modified CCR5 infusions. The Trenton patient (the heterozygote who went non detectable while off meds in the first Phase I trial) went non detectable after an 11 weeks treatment interruption.

Since late last week the stock has risen approximately 15% or so on very high volume with no news.  None.  Hmmmm.

Just sayin. 
Beware Romanians bearing strange gifts

Offline Rev. Moon

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #278 on: June 18, 2012, 09:11:16 PM »
Grassy knoll territory:

This week will be 12 weeks since the first 4 heterozygote participants in the latest Phase II Sangamo zinc finger trial stopped their medications after the modified CCR5 infusions. The Trenton patient (the heterozygote who went non detectable while off meds in the first Phase I trial) went non detectable after an 11 weeks treatment interruption.

Since late last week the stock has risen approximately 15% or so on very high volume with no news.  None.  Hmmmm.

Just sayin.

It's teh cure, Willie!!  Let us party!
"I have tried hard--but life is difficult, and I am a very useless person. I can hardly be said to have an independent existence. I was just a screw or a cog in the great machine I called life, and when I dropped out of it I found I was of no use anywhere else."

Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #279 on: June 18, 2012, 09:22:17 PM »
It's teh cure, Willie!!  Let us party!

Lol...one of these days, my friend...one of these days.


Beware Romanians bearing strange gifts

Offline Solo_LTSurvivor

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #280 on: June 18, 2012, 09:59:03 PM »
It's teh cure, Willie!!  Let us party!

Be careful or you just might have a myocardial infarction.
don't equate intelligence with lack of masculinity
Jim Phelps, Mission Impossible
____________________________

Seroconverted: Early 80s
Tested & confirmed what I already knew: early 90s

Current regimen: Atripla. 
Last regimen:  Epzicom, Sustiva (since its inception with NO adverse side effects: no vivid dreams and NONE of the problems people who can't tolerate this drug may experience: color me lucky ::))
Past regimens
Fun stuff (in the past):  HAV/HBV, crypto, shingles, AIDS, PCP

Jan 2012: 818/21%
Apr 2012: 964/22%
Jul. 2012: 890/21%
Oct. 2012: 920/23%

Still UD after all these years

Offline alexjones

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #281 on: June 18, 2012, 10:33:43 PM »
Oh boy, hopefully big news expected!!!! :D :D

Offline Rev. Moon

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #282 on: June 18, 2012, 10:40:01 PM »
Be careful or you just might have a myocardial infarction.


OEMGEE, my left nipple is itchy.  Do you think that's a bad sign?
"I have tried hard--but life is difficult, and I am a very useless person. I can hardly be said to have an independent existence. I was just a screw or a cog in the great machine I called life, and when I dropped out of it I found I was of no use anywhere else."

Offline LM

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #283 on: June 18, 2012, 10:42:45 PM »
I'm a bit confused. I read this article and it says Sangamo will begin human trials only in 2014... and I'm like... wha??

Are they talking about different things or what? Here's the article: http://www.sacbee.com/2012/06/17/4565860/hiv-cure-in-works-but-issue-is.html

Offline buginme2

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #284 on: June 18, 2012, 11:00:59 PM »
I'm a bit confused. I read this article and it says Sangamo will begin human trials only in 2014... and I'm like... wha??

Are they talking about different things or what? Here's the article: http://www.sacbee.com/2012/06/17/4565860/hiv-cure-in-works-but-issue-is.html

Ya, it's different.  The current Sangamo trial is testing if they can remove cd4 cells and modify them to make the person resistant to HIV (no one thinks this will work and hasn't as of yet).

The study they are talking about in the article is to do basically the same thing except using stem cells instead of cd4 cells.  That testing won't start for a few more years and even if it is successfull will take at least a decade or two to complete.


So really no need to get all worked up about some treatment that is two decades away. 


Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #285 on: June 18, 2012, 11:25:40 PM »
Ya, it's different.  The current Sangamo trial is testing if they can remove cd4 cells and modify them to make the person resistant to HIV (no one thinks this will work and hasn't as of yet).

The study they are talking about in the article is to do basically the same thing except using stem cells instead of cd4 cells.  That testing won't start for a few more years and even if it is successfull will take at least a decade or two to complete.

So really no need to get all worked up about some treatment that is two decades away.

Tell that to the Trenton patient. 
Beware Romanians bearing strange gifts

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #286 on: June 18, 2012, 11:39:16 PM »
The Trenton patient (a heterozygote) went undetectable at 11 weeks with one infusion of Sangamo-modified T-Cells.  Unfortunately his test results came back after week 12, when the trial ended.  He went back on meds without knowing he was undetectable.

As we've talked about here, Sangamo is trying to replicate the Trenton patient's experience in the current trial with heterozygotes.  Someone knows if this is working or not -- they've been off meds now for at least 12 weeks.  The second trial is for non-heteros, with a dose of Cytoxan which will suppress your own T-Cells to create "space" for the modified one.  Again, someone knows if this is working or not -- since it's been several months since the first patients were infused.

I wanted to participate, but a) I'm not a hetero and b) my numbers weren't good enough for the second trial (even though they were pretty good).  Perhaps they are cherry-picking patients to try to get the best possible outcomes.  Or they weren't getting the results they wanted so they changed the criteria -- I don't know.

If the T-Cells work great!  But as a "Plan B", I think the stem cell treatment will work.  If it's in trials in 2014 I'd say that's pretty  fast.  CIRM (the CA-based publicly funded stem cell agency) needs a "win" to justify the public money being spent.    Also, CalImmune is working on a stem cell trial -- I'm being screened for that one, too. That one takes place this summer.

PS -- Sangamo (SGMO) is a volatile biotech stock.  After being down 57% last year (due to a failure of a diabetic neuropathy trial) it's up 92% this year.  It's leading product is the HIV T-Cell treatment that I've been talking about)  Hmmmm.....

« Last Edit: June 18, 2012, 11:43:39 PM by geobee »

Offline xman

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #287 on: June 19, 2012, 01:23:20 PM »
Ya, it's different.  The current Sangamo trial is testing if they can remove cd4 cells and modify them to make the person resistant to HIV (no one thinks this will work and hasn't as of yet).

The study they are talking about in the article is to do basically the same thing except using stem cells instead of cd4 cells.  That testing won't start for a few more years and even if it is successfull will take at least a decade or two to complete.


So really no need to get all worked up about some treatment that is two decades away.

i think it will take less to find a functional cure. total eradication might be more difficult but with a combination of therapeutic vaccines and drugs able to reverse latency it is possible to kill definitely the virus without a stem cell transplant.
« Last Edit: June 19, 2012, 01:28:16 PM by xman »
sign the petition launched by the aids policy project addressed to the nih aimed to increase the money needed to find the cure:

http://www.aidspolicyproject.org/petition_for_the_nih

we can make a difference and we need to fight. please support them! it doesn't cost you anything. they need it now more than ever!

Offline buginme2

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #288 on: June 19, 2012, 01:29:15 PM »
i don't think it will take 2 decades, at least for a functional cure. total eradication might be more difficult but with a combination of therapeutic vaccines and drugs able to reverse latency it is possible to kill definitely the virus without a stem cell transplant.

That's not the point of this thread or the specific post I was replying to. 

We were speaking a the Sangamo stem cell trials, which yes can take up to two decades.

Offline xman

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #289 on: June 19, 2012, 01:41:46 PM »
That's not the point of this thread or the specific post I was replying to. 

We were speaking a the Sangamo stem cell trials, which yes can take up to two decades.

ok, sorry. what i mean is if there's something else why continue on stem cells? we don't even know if hsc are infected by the virus. according to a recent study they are not.
sign the petition launched by the aids policy project addressed to the nih aimed to increase the money needed to find the cure:

http://www.aidspolicyproject.org/petition_for_the_nih

we can make a difference and we need to fight. please support them! it doesn't cost you anything. they need it now more than ever!

Offline LM

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #290 on: June 19, 2012, 01:58:38 PM »
I'm happy with waiting, as long as it works. Let's all be healthy till then.  :)

Offline buginme2

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #291 on: June 19, 2012, 02:32:30 PM »
ok, sorry. what i mean is if there's something else why continue on stem cells? we don't even know if hsc are infected by the virus. according to a recent study they are not.

Well, the thing about HSC is they Turn into cd4 cells.  If the are programmed to be without the ccr5 gene then you would have an ongoing and lifetime supply of cd4 cells resistant to HIV. 

The current trials that they are doing, removing cd4 cells and deleting the gene, theoretically would only work on the cd4 cells you treat.  The other cells your body makes would still be able to be infected with HIV, that's why changing stem cells seems like a more viable option.

Now, stem cell therapy is a new science (relatively) and deleting genes from stem cells is very new.  You can bet your last dollar that the FDA is going to make sure that 1. It works and 2. There are no unintended consequences before the approve the therapy.  Especially since HIv can be controlled currently using antiretroviral drugs. 

That's why I say, and that article someone posted earlier said, it will be decades before this therapy pans out.

Vaccines and eradication trials, that's a completely different set of circumstances.

« Last Edit: June 19, 2012, 02:35:41 PM by buginme2 »

Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #292 on: June 19, 2012, 03:12:33 PM »
it will be decades before this therapy pans out.

Better call Sangamo and Callimune and tell them to save their money.
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Offline freewillie99

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #293 on: July 01, 2012, 02:18:47 PM »
Cue angst:

http://medicalxpress.com/news/2012-07-scientists-alternative-gene-therapy-technique.html

Scientists develop alternative to gene therapy: The technique points to safer, simpler potential HIV treatment

July 1, 2012 in Medical research

Scientists at The Scripps Research Institute have discovered a surprisingly simple and safe method to disrupt specific genes within cells. The scientists highlighted the medical potential of the new technique by demonstrating its use as a safer alternative to an experimental gene therapy against HIV infection.

"We showed that we can modify the genomes of cells without the troubles that have long been linked to traditional gene therapy techniques," said the study's senior author Carlos F. Barbas III, who is the Janet and Keith Kellogg II Professor of Molecular Biology and Chemistry at The Scripps Research Institute.

The new technique, reported in Nature Methods on July 1, 2012, employs zinc finger nuclease (ZFN) proteins, which can bind and cut DNA at precisely defined locations in the genome. ZFNs are coming into widespread use in scientific experiments and potential disease treatments, but typically are delivered into cells using potentially risky gene therapy methods.

The Scripps Research scientists simply added ZFN proteins directly to cells in a lab dish and found that the proteins crossed into the cells and performed their gene-cutting functions with high efficiency and minimal collateral damage.

"This work removes a major bottleneck in the efficient use of ZFN proteins as a gene therapy tool in humans," said Michael K. Reddy, who oversees transcription mechanism grants at the National Institutes of Health's (NIH) National Institute of General Medical Sciences, which helped fund the work, along with an NIH Director's Pioneer Award. "The directness of Dr. Barbas's approach of 'simply' testing the notion that ZFNs could possess an intrinsic cell-penetrating ability is a testament to his highly creative nature and further validates his selection as a 2010 recipient of an NIH Director's Pioneer Award."

Questioning Assumptions

ZFNs, invented in the mid-1990s, are artificial constructs made of two types of protein: a "zinc-finger" structure that can be designed to bind to a specific short DNA sequence, and a nuclease enzyme that will cut DNA at that binding site in a way that cells can't repair easily. The original technology to make designer zinc finger proteins that are used to direct nucleases to their target genes was first invented by Barbas in the early 1990s.

Scientists had assumed that ZFN proteins cannot cross cell membranes, so the standard ZFN delivery method has been a gene-therapy technique employing a relatively harmless virus to carry a designer ZFN gene into cells. Once inside, the ZFN gene starts producing ZFN proteins, which seek and destroy their target gene within the cellular DNA.

One risk of the gene-therapy approach is that viral DNA—even if the virus is not a retrovirus—may end up being incorporated randomly into cellular DNA, disrupting a valuable gene such as a tumor-suppressor gene. Another risk with this delivery method is that ZFN genes will end up producing too many ZFN proteins, resulting in a high number of "off-target" DNA cuts. "The viral delivery approach involves a lot of off-target damage," said Barbas.

In the new study, Barbas and his colleagues set out to find a safer ZFN delivery method that didn't involve the introduction of viruses or other genetic material into cells. They experimented initially with ZFN proteins that carry extra protein segments to help them penetrate cell membranes, but found these modified ZFNs hard to produce in useful quantities. Eventually, the scientists recognized that the zinc-finger segments of ordinary ZFNs have properties that might enable the proteins to get through cell membranes on their own.

"We tried working with unmodified ZFNs, and lo and behold, they were easy to produce and entered cells quite efficiently," Barbas said.

New Strategy Against HIV

Next, the team showed how the new technique could be used in a ZFN-based strategy against HIV infection.

The AIDS-causing retrovirus normally infects T cells via a T cell surface receptor called CCR5, and removing this receptor makes T cells highly resistant to HIV infection. In 2006, an HIV patient in Berlin lost all signs of infection soon after receiving a bone marrow transplant to treat his leukemia from a donor with a CCR5 gene variant that results in low expression of the receptor. Disrupting the CCR5 gene in T cells with a ZFN-based therapy might be able to reproduce this dramatic effect.

"The idea is to protect some of the patient's T cells from HIV, so that the immune system remains strong enough ultimately to wipe out the infection," said Barbas.
A gene therapy that uses ZFNs to disrupt CCR5 genes in T cells and reinfuses the modified T cells into patients is currently in clinical trials. Barbas and his team showed that they could achieve the same effect with their simpler ZFN-delivery method. They added ZFN proteins directly to human T cells in a culture dish and found that within hours, a significant fraction of the ZFN-treated cells showed sharp reductions in CCR5 gene activity.

After several applications of ZFNs, aided by a special cooling method that improves the ability of the proteins to get across cell membranes, the scientists were able to inactivate CCR5 genes with an efficiency approximating that of the gene therapy-based approach, Barbas said.

The new approach also appeared to be safer. A DNA-based method the team used for comparison or the viral-based methods reported in the literature by others ended up producing ZFNs for up to several days, causing a significant amount of off-target DNA damage. But the directly delivered ZFN proteins remained intact within cells for only a few hours, causing minimal off-target damage.

"At some off-target locations where the gene therapy approach frequently causes damage, we saw no damage at all from this new technique," said Barbas.

Hope for 'Tiny Factories' of Health

The team tested its direct ZFN-delivery technique with a variety of other cell types and found that it works with particularly high efficiency in human skin "fibroblast" cells. Researchers now are working on advanced therapies in which they harvest such fibroblasts from patients and reprogram the cells' gene-expression patterns so that they effectively become stem cells. These induced stem cells can then be modified using ZFNs and other genome-editing techniques. When reinfused into a patient, they can produce millions of therapeutic progeny cells over long periods.

Such techniques may one day be used to treat a vast array of diseases. Barbas, who has been developing anti-CCR5 strategies for more than a decade, wants to start with a ZFN-based therapy that disrupts the CCR5 gene in hematopoietic stem cells. These blood-cell-making stem cells, reinfused into an HIV patient, would become tiny factories for producing HIV-resistant T cells.

"Even a small number of stem cells that carry this HIV-resistance feature could end up completely replacing a patient's original and vulnerable T cell population," he said.
« Last Edit: July 01, 2012, 02:23:23 PM by freewillie99 »
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Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #294 on: July 02, 2012, 11:28:25 AM »
Thank you for posting this article.

What fascinating science this is -- short lived proteins that change your DNA and make your cells resistant to HIV?  Wow. 

[Changed Below]

I've been thinking a lot about this approach vs. the viral vector approach.  This approach has many advantages --

-- It's a modification of stem cells, not T-Cells
-- Fewer off target effects
-- It's relatively easy to transform skin cells to stem cells
-- It's a relatively easy (apparently) to make the stem cells immune to HIV
-- Just a small pool of modified stem cells is all you made need
-- No need to worry about ABs to the viral vector
-- You could repeat the process (vectors make ABs which take time to disappear)

I was getting a little discouraged about the T-Cell approach and have read a few things that hinted that it was difficult to work with stem cells.  So I was souring on the whole ZFN idea. But this latest development is a wow! that could, IMHO, lead to a functional cure. 



« Last Edit: July 03, 2012, 01:43:14 PM by geobee »

Offline anonomous

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #295 on: July 12, 2012, 09:39:38 AM »
Hi To all

Is this for real or is it like all the other so called cures? I dont know what to believe there are so many stories but with no potential hope behind them,we all have this virus that threatens our lives everyday and all we are getting is false media and hope that never seems to come.

Please can someone tell me if this is for real im tired of false hope and living with this damn virus i just want to be normal again is that so much to ask lol.

Offline geobee

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #296 on: July 12, 2012, 10:32:12 AM »
I think this is for real but it could be years before we see it in the clinic.   For myself, I act as if I'll have HIV forever.  A cure may come along, but I'm sure going to take care of myself (take my meds, see the doc, exercise, etc.) in the meantime.

I just listened to the Sangamo investor call.  Not much news there except that there should be an update on the HIV trial at the end of July.  The CEO (Ed Lamphier) did say it was relatively easy to recruit for the trials, which I thought was interesting.

Offline misterprice

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #297 on: July 12, 2012, 11:59:32 AM »

 
Also, ah, That Cd4 cells die out with in an X amount of time... Nothing new. Now Stem Cells do not die out and are always multiplying. Sooooo, for a cure:  1) More is better: the more cells without the CCR5 receptor the better. Knocking-out both receptors (CCR5 and CX4) would be best. 2) Stm Cells SEEM far more superior then cd4s for a CURE. Do we need both of these for a cure of sorts? Nobody knows for sure. Scientist stopped finding HIV In Brown a few months after the transplant...but he had virtually a new immune system after the treatment. The Trenton patient went undetected with just a few percent of his CD4s being zinc fingered...:).... don't get carried away AND please incluye a link next time. :P                                                                                                                    And another thing, would'nt count  on any one technique as being capable in and of itself in getting us to a cure. A combination of Medication + gen therapy + therapeutic vaccines will be a good bet. ciao.

Yeah, knocking-out both receptors (CCR5 and CXCR4) would be the best, in order to have an impaired immune system. I hope you do realize that, in order to work, the immune system needs to be able to comunicate through chemokine signaling; therefore, both receptors are required to modulate the recruitment of human leukocytes during the inflammatory response in order to fight potential diseases.
« Last Edit: July 12, 2012, 03:28:04 PM by misterprice »

Offline leatherman

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #298 on: July 12, 2012, 01:15:20 PM »
Please can someone tell me if this is for real im tired of false hope and living with this damn virus i just want to be normal again is that so much to ask lol.
a couple* of thoughts
(that's a Southern "couple" which means more than 1 and not necessarily 2 ROFL)

1) this thread started just about 4 yrs ago, and seeing how far along things have moved, I would suggest that you don't hold your breath waiting for this one. ;D Oh, not that it might not turn out to be the cure, it's just that science takes a long time. HIV is a retrovirus, which was little known when the epidemic started, and science has already made HUGE leaps towards understanding this and controlling this. (Look at the amazing meds we're taking today - they're a far cry from AZT) It's just going to take a long time to find a "cure", so you'll need to learn patience - like we all have. Why, I've been waiting on a cure for 3 decades, you know, while they keep saying they'll have a cure in "10 yrs". ::) (IMHO, a vaccine will probably show up before a "cure" anyway.)

2) so few diseases/viruses have actually been cured, I'm not really certain why anyone should expect HIV, a relatively "new" disease, to be cured before things that have studied and researched for decades longer. That's not to say that we shouldn't "hope for a cure" (Hey Hopey my friend, did you see what I did there? LOL) but you're going to need to plan on how you're going to live your life for a looooong time before a cure comes along. That means dealing with meds, access to health care, possible side effects, etc, along with daily life and planning for retirement.

3)Since it's going to take some time that means you'll also need to work on having a better attitude. How are you not "normal" now? (besides, just what is "normal" anyway?) Lots of people have lots of diseases and continue to live their "normal" lives, just taking the extra measures it takes to deal with their health issues, emotional issues, handicaps, etc. (Personally, although I do deal with HIV everyday, I wouldn't say that I'm "threatened" by it. The meds I'm taking have kept it in check for many years now.) Don't let HIV have more power in your life than it deserves - that's just stigmatizing yourself. (lordy there are enough haters in the world to stigmatize you without doing it to yourself. LOL ;D)

4) Finally just because this (zinc fingers stuff) hasn't turned into the cure, doesn't mean it's a false hope. The research forum is filled with info about all sorts of ways scientists are looking for the cure. I'd like to think that at least one of them is the path to the cure. ;) As mentioned it may even take a combination of methods to create the "cure". In the meantime, the catch is you just can't hang out here, wasting away your days, hoping the next post is the post about the cure. Quite frankly, none of the science seems to be far enough along for that to even be a remote possibility. But coming to the research thread and seeing how far along each of these incredible methods is (zinc fingers, getting rid of the reservoirs, stem cell transplants, vaccines, PrEP and PEP, etc - not to mention the research of new meds and improvements to the old meds) should give you lots of hope (about better meds in the future, about a cure), things to think about, and some knowledge to use to either help fund research or to talk to your legislators about so that they can properly fund the necessary projects.

I hope what I've posted can help you can understand that, while we have to live with the virus everyday, that we're all still "normal" and that in the future,  thanks to a lot of science, there will be even better HIV meds, a vaccine and, with some luck maybe even a cure. ;)
leatherman (aka mIkIE)


chart from 1992-2013; updated 2/09/13  Reyataz/Norvir/Truvada

Offline misterprice

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Re: Zinc Finger Proteins Put Personalized HIV Therapy Within Reach
« Reply #299 on: July 12, 2012, 04:25:11 PM »
Hi To all

Is this for real or is it like all the other so called cures? I dont know what to believe there are so many stories but with no potential hope behind them,we all have this virus that threatens our lives everyday and all we are getting is false media and hope that never seems to come.

Please can someone tell me if this is for real im tired of false hope and living with this damn virus i just want to be normal again is that so much to ask lol.

Well, the idea itself seems very dangerous to me. The CCR5 receptor regulates trafficking and effector functions in memory/effector T-lymphocytes, and it plays an essential role in the inflammatory response. Destroying the CCR5 receptor could have catastrophic consequences for the proper functioning of the immune system. In addition, this would not offer protection against X4 strains.

« Last Edit: July 12, 2012, 04:47:42 PM by misterprice »

 


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